Mucosal surfaces are unique relative to other sites in the body in that they possess defense mechanisms that act "outside" the body. The overall goal of these studies is to define the role of luminal host defense mechanisms in the pathogenesis of infections of the human intestinal tract with enteric pathogens. The studies will use two clinically important enteric pathogens that do not invade the intestinal mucosa., Giardia lamblia and Cryptosporidium parvum. Both pathogens cause mucosal disease accompanied by diarrhea, and infections are usually self-limited in a immunocompetent host, but can become chronic and debilitating in the presence of underlying immune dysfunction. They differ in that C. parvum infect in associated with moderate to severe mucosal inflammation, while Giardia typically cause little or no inflammation. The studies will test the hypothesis that nitric oxide (NO), defensins, and IgA are luminal defense mechanisms which play a key role in controlling and eliminating infection with C. parvum and Giardia. In addition, the role of prostaglandin production will be defined in regulating mucosal inflammation after C. parvum infection. Aim 1 will be to define the role of prostaglandins, nitric oxide, and defensins in the mucosal immune response to C. parvum. Aim 2 will be to characterize the role of luminal host defense mechanisms (NO, defensins, IgA) in the pathogenesis of Giardia infection. The studies will focus particularly on the role of intestinal epithelial cells in the interaction between infecting pathogen and host, since these cells play a key role in the expression or final delivery of all three luminal effector mechanisms, and are the host cells that predominantly come in contact with these pathogens. The studies will employ complementary in vitro and in vivo approaches as model systems, using intestinal epithelial cell lines, human intestinal xenografts in SCID mice, and normal and knock-out mice. The findings of these studies will provide important new insights into physiologically relevant luminal host effector mechanisms that control infection with clinically important human enteric pathogens.